Circuit-level mechanisms of memory consolidation

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Understanding memory is a central goal of neuroscience, with potentially far-reaching consequences for treating Alzheimer's disease and other dementias. Memory formation requires 'offline consolidation', whereby the neuronal traces representing newly-acquired experiences are selectively stabilised during sleep. Following their retrieval, consolidated memories undergo an additional process of reconsolidation that further stabilizes them for long-term expression.Damage to particular brain regions results in selective behavioural impairments. The hippocampus, for example, encodes new memories about specific events and places (episodic and spatial memories). We lack a comprehensive understanding of how new memories gain long-term expression but two distinctive patterns of hippocampal electrical activity could promote consolidation processes: sharp-wave ripples (SWRs) and 'dentate spikes'. SWRs have received much scientific attention, and disrupting SWRs impairs memory. In contrast, little is known about dentate spikes, a misleading term that refers not to the action potentials of individual dentate granule cells (DGCs) but to a large population event that recruits many DGCs. No one has ever silenced dentate spikes to determine their role in memory. Our proposed experiments will address this important gap in our knowledge, using cutting-edge technology to detect and silence dentate spikes in the mouse brain in post-learning sleep, thereby revealing their contribution to memory consolidation.Our approach will utilise sophisticated genetic approaches that can deliver light-sensitive proteins into particular neurons (e.g. DGCs). When stimulated by light, these proteins will silence or activate those neurons. We will use real-time detection of dentate spikes to trigger light-stimulation, giving us precise control over neuronal activity during sleep.We will assess the contribution of dentate spikes to two distinct forms of memory, both of which require the hippocampus. First we will investigate the effects of dentate spike silencing on associative memory, e.g. learning that cue A predicts outcome X. Ordinarily, learning simple associations does not require the hippocampus, but if the relationship is made ambiguous (e.g. such that outcome X only follows cue A on a subset of trials), the hippocampus then becomes necessary. Second, we will investigate the effects of silencing dentate spikes on non-associative memories, e.g. using the relative novelty or familiarity of mnemonic cues to guide behavioural choices. Consolidation is thought to be critical for associative but not non-associative memories. If silencing dentate spikes also affects non-associative memory, this would suggest a more general role in memory, rather than in consolidation per se. Moreover, in control conditions we will silence DGCs during sleep but NOT during dentate spikes to see whether this also affects memory consolidation.Next, we will determine the neuronal inputs driving dentate spikes. We will use a recently developed technique to selectively target neurons in the neocortex that project directly to DGCs and determine how activating or silencing those neocortical cells alters dentate spikes.Finally, we will test how inhibiting an already consolidated memory during 'reconsolidation' affects its long-term expression. We will use a special genetically-modified mouse line that can drive the expression of a light-sensitive neuronal inhibitor selectively in cells that were active during a particular learning episode. At a later time we will reactivate this memory, which places the memory in a labile state, and then determine how inhibiting dentate spikes following this reactivation affects the reconsolidation of this memory.Collectively, our experiments will make a major contribution to a comprehensive understanding of the circuit-level mechanisms underlying the long-lasting expression of memory.